Epilepsy is the third most prevalent neurological disorder after stroke and Alzheimer's disease with an incidence of 1 in 26 individuals. Epileptogenesis refers to the progressive decrease in seizure threshold that ultimately results in unprovoked, spontaneous seizures that may increase in frequency, severity and duration. Though there are a number of anti-convulsant drugs available, there are no anti-epileptogenic drugs that mitigate the progression of the disease. Long-term changes in gene expression that are associated with epileptogenesis imply that one or more master regulators of transcription may be coordinating the brain alterations. In order to uncover these genetic mechanisms, we turned to the genome-wide expression datasets generated by the Epilepsy Microarray Consortium. The datasets consist of mRNA expression profiles of mouse dentate granule cells assayed at various time points after Status Epilepticus (S.E). Because these datasets are derived from brains induced by 3 different convulsant stimuli, each in 2 different labs, and at various time-points, this gives us the opportunity to discern model-independent and lab-independent alterations in gene networks. We used an innovative and novel bioinformatics tool developed by us to reveal the transcription factors and nuclear proteins that drive gene changes observed in the Epilepsy Consortium dataset. We found that a master epigenetic complex called Polycomb drives the majority of gene changes across labs, models and time. This is exciting because Polycomb is a well-known driver of life-long changes in gene expression that works by epigenetically silencing genes during body plan establishment across the phyla. Our preliminary data shows that the epigenetic mark uniquely catalyzed by Polycomb is induced in the hippocampus within 24hrs after seizures and remains at least 5 days after the seizure. In this proposal we will test the hypothesis that an alteration in Polycomb output is a principle modifier of epileptogenesis: we will determine whether the increase in Polycomb activity is pathological or protective. We will test whether pharmacological modulation of Polycomb can alter the process of epileptogenesis and thus potentially identify a novel class of drugs. Small molecule inhibitors of Polycomb such as those in clinical trials for lymphoma will be tested for their efficacy in stalling epileptogenesis. We anticipate that these studies will establish Polycomb as a major orchestrator of the long-term changes associated with epileptogenesis. If so, approaches that modulate Polycomb function may be of benefit to the 65 million people world- wide that live with epilepsy.